Delivery systems

ABSTRACT

A delivery system comprising a covering having at least two compartments is provided. A first compartment contains a first therapeutic agent and the second compartment can be unfilled and is configured to receive a second therapeutic agent. The first compartment and the second compartment are separated by at least one removable separation member, for example a drawstring, that can be pulled to allow the first and second therapeutic agents to mix prior to delivery at a selected surgical site. Either the first or second compartment of the covering define an opening further comprising a pre-attached sealing member, which can be a flap sealable by heat, sutures, pressing or interference fittings. The opening of the empty compartment can be configured to receive a filling member, such as a funnel fitted with a spring loaded clip for temporary attachment to the covering. A method of treating a bone defect in a patient utilizing the delivery system is also provided.

FIELD

A delivery system for delivering therapeutic agents to a surgical siteis provided. More particularly, the delivery system includes a coveringhaving separate compartments for combining demineralized bone particleswith grafting materials, the covering configured for containing andmixing the therapeutic agents prior to delivery at a surgical site.

BACKGROUND

The use of bone grafts and bone substitute materials in orthopedicmedicine is known. While bone wounds can regenerate without theformation of scar tissue, fractures and other orthopedic injuries take along time to heal, during which time the bone is unable to supportphysiologic loading unaided. Metal pins, screws, rods, plates and meshesare frequently required to replace the mechanical functions of injuredbone. However, metal is significantly more stiff than bone. Use of metalimplants may result in decreased bone density around the implant sitedue to stress shielding. Physiologic stresses and corrosion may causemetal implants to fracture. Unlike bone, which can heal small damagecracks through remodeling to prevent more extensive damage and failure,damaged metal implants can only be replaced or removed. The naturalcellular healing and remodeling mechanisms of the body coordinateremoval of bone and bone grafts by osteoclast cells and formation ofbone by osteoblast cells.

Conventionally, bone tissue regeneration is achieved by filling a bonerepair site with a bone graft. Over time, the bone graft is incorporatedby the host and new bone remodels the bone graft. In order to place thebone graft, it is common to use a monolithic bone graft or to form anosteoimplant comprising particulated bone in a carrier. The carrier isthus chosen to be biocompatible, to be resorbable, and to have releasecharacteristics such that the bone graft is accessible.

The rapid and effective repair of bone defects caused by injury,disease, wounds, or surgery is a goal of orthopedic surgery. Toward thisend, a number of compositions and materials have been used or proposedfor use in the repair of bone defects. The biological, physical, andmechanical properties of the compositions and materials are among themajor factors influencing their suitability and performance in variousorthopedic applications.

Demineralized bone matrix (DBM) implants have been reported to beparticularly useful. Demineralized bone matrix is typically derived fromcadavers. The bone is removed aseptically and/or treated to kill anyinfectious agents. The bone is then particulated by milling or grindingand then the mineral components are extracted for example, by soakingthe bone in an acidic solution.

Some DBM formulations have various drawbacks. For example, while thecollagen-based matrix of DBM is relatively stable, the active factorswithin the DBM matrix are rapidly degraded. The osteogenic activity ofthe DBM may be significantly degraded within 24 hours afterimplantation, and in some instances the osteogenic activity may beinactivated within 6 hours. Therefore, the factors associated with theDBM are only available to recruit cells to the site of injury for ashort time after transplantation. For much of the healing process, whichmay take weeks to months, the implanted material may provide little orno assistance in recruiting cells.

Attempts to overcome these problems have lead researchers to utilizedelivery systems such as polymer mesh bags to release DBM at a surgicalsite. However, any additional bone graft material, such as for example,autologous bone or growth factors, would have to be placed underneath oron top of the DBM mesh bag which approach is, typically, not recommendedfor inducing new bone formation.

Thus, there is a need to improve the efficacy and consistency of DBMdelivery systems by mixing the DBM particles/fibers with other bonegraft materials such as autologous bone and other therapeutic agentsthroughout the mesh bag prior to, during or after the surgicalprocedure. It would therefore be desirable to provide delivery systemsthat are configured to allow live cells and other therapeutic agents tobe in close contact with DBM particles/fibers so as to induce bonegrowth throughout the graft material rather than primarily along thesurface of the DBM containing delivery system.

SUMMARY

Accordingly, a delivery system for delivering DBM mixed with one or moretherapeutic agents is provided. Generally, the delivery system comprisesa covering having at least two compartments, a first compartmentcontaining a first therapeutic agent and a second compartment configuredto receive a second therapeutic agent. The first compartment and thesecond compartment are separated by at least one removable temporaryseparation member, for example a drawstring that can be pulled to allowthe first and second therapeutic agents to mix prior to delivery at aselected surgical site.

Either the first or the second compartment can be provided unfilled.Either the first or second compartment of the covering define an openingfurther comprising a pre-attached sealing member. In severalembodiments, the sealing member can be a flap sealable by heat, sutures,pressing or interference fittings. The opening of the empty compartmentcan be configured to receive a filling member for filling the emptycompartment with a therapeutic agent such as autograft material. Invarious embodiments, the filling member can be a funnel, a spoon, asyringe or any device that can function to fill the empty compartmentwith a therapeutic agent. The delivery system provided in thisdisclosure further comprises an attachment element cooperativelyattached to the filling member or the covering in order to maintain theempty or second compartment open for filling with a second therapeuticagent. In some aspects, the attachment element can be a spring loadedclip, a friction or an interference fitting.

In various embodiments, the first therapeutic agent placed in the firstcompartment comprises demineralized bone matrix and the secondtherapeutic agent placed in the second compartment comprises a protein(e.g., bone morphogenetic protein) carbohydrate, lipids, collagen,allograft bone, autograft bone, tricalcium phosphate, hydroxyapatite,growth and differentiation factors, carriers for growth factors, growthfactors extracts of tissue, bone marrow aspirate, concentrates of lipidderived or marrow derived adult stem cells, umbilical cord derived stemcells, committed or partially committed cells from osteogenic orchondrogenic lineage, antimicrobials, antibiotics, statins, orcombinations thereof.

In other embodiments, the present disclosure provides a delivery systemincluding a covering configured for implantation into a bone defectsite. The covering can have at least two compartments, a firstcompartment containing a first therapeutic agent, for example DBM and asecond unfilled compartment configured to receive a second therapeuticagent, wherein the covering retains the first therapeutic agent formixing with the second therapeutic agent prior to delivery at a surgicalsite. The at least two compartments of the covering can be separated byat least one removable temporary separation member, the secondcompartment defining an opening further comprising a pre-attachedsealing member. The pre-attached sealing member comprises a flapsealable by sutures, heat or any other sealing means. The deliverysystem can be a porous mesh and includes an attachable filling memberconfigured to fit over the opening of the second empty compartment forfilling with a therapeutic agent such as autograft. The filling memberalso includes an attachment member that can be, in some aspects, aspring loaded clip, a friction or interference fitting. The temporaryseparation member can be removed to allow for the first and secondtherapeutic agents to mix thoroughly prior to delivery at a surgicalsite.

In various embodiments, a method of treating a bone defect in a patientin need of such treatment is provided. The method described in thisdisclosure comprises implanting into the bone defect a delivery systemcomprising a covering having at least two compartments, a firstcompartment containing a first therapeutic agent and a secondcompartment configured to receive a second therapeutic agent, whereinthe covering retains the first therapeutic agent for mixing with thesecond therapeutic agent prior to delivery at a surgical site, the atleast two compartments being separated by at least one removableseparation member, the second compartment defining an opening furthercomprising a pre-attached sealing member.

In other aspects, the method of treating the bone defect furthercomprises the step of mixing of the first and second therapeutic agentsby removing the removable separation member, for example a drawstring.In certain embodiments, the method of treating the bone defect canfurther include the step of shrinking or reducing in size the deliverysystem by removing the removable separation member. In various aspects,the method of treating a bone defect further includes attaching afilling member, for example a funnel, to the unfilled compartment, thefilling member including an attachment member such as a spring loadedclip, a friction or interference fitting.

In some embodiments, the elongated containment portion of the coveringhas a cross sectional shape selected from generally circular orgenerally oval and a shape that can be tubular, rectangular, or cubic.The covering can have two ends opposite each other and sides connectedto the two ends defining a cylinder, rectangle, tube or other volumetricforms. The covering can be made from porous mesh to provide, forexample, a porous mesh bag.

In some embodiments, some of the compartments are unfilled atmanufacture but are configured to be filled prior to or during thesurgical procedure.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a side view of a delivery system comprising acovering having three compartments in accordance with one embodiment ofthe present disclosure;

FIG. 2 illustrates a top view of a delivery system comprising a coveringalso having three compartments in accordance with another embodiment ofthe present disclosure;

FIG. 3 illustrates a side view of a delivery system including a coveringhaving two compartments in accordance with another embodiment of thepresent disclosure; and

FIG. 4 illustrates a side view of a filling member in accordance with anembodiment of the present disclosure.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

Definitions

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. For example,reference to “a compartment” includes one, two, three or morecompartments.

“Therapeutic agent or bioactive compound,” as used herein, refers to acompound or entity that alters, inhibits, activates, or otherwiseaffects biological or chemical events. For example, bioactive agents mayinclude, but are not limited to, osteogenic or chondrogenic proteins orpeptides, anti-AIDS therapeutic agents, anti-cancer therapeutic agents,antibiotics, immunosuppressants, anti-viral therapeutic agents, enzymeinhibitors, hormones, neurotoxins, opioids, hypnotics, anti-histamines,lubricants, tranquilizers, anti-convulsants, muscle relaxants andanti-Parkinson therapeutic agents, anti-spasmodics and musclecontractants including channel blockers, miotics and anti-cholinergics,anti-glaucoma compounds, anti-parasite and/or anti-protozoal compounds,modulators of cell-extracellular matrix interactions including cellgrowth inhibitors and antiadhesion molecules, vasodilating agents,inhibitors of DNA, RNA or protein synthesis, anti-hypertensives,analgesics, anti-pyretics, steroidal and non-steroidal anti-inflammatoryagents, anti-angiogenic factors, angiogenic factors, anti-secretoryfactors, anticoagulants and/or antithrombotic agents, local anesthetics,ophthalmics, prostaglandins, anti-depressants, anti-psychotictherapeutic agents, anti-emetics, and imaging agents. In certainembodiments, the bioactive agent is a drug. The therapeutic agent, insome embodiments, can include bone, bone cells, other cells, bonesubstitutes, DBM, or the like. In some embodiments, the bioactive agentor therapeutic agent is a growth factor, cytokine, extracellular matrixmolecule or a fragment or derivative thereof, for example, a cellattachment sequence such as RGD.

“Biocompatible,” as used herein, refers to materials that, uponadministration in vivo, do not induce undesirable long-term effects.

“Bone,” as used herein, refers to bone that is cortical, cancellous orcortico-cancellous of autogenous, allogenic, xenogenic, or transgenicorigin.

“Demineralized,” as used herein, refers to any material generated byremoving mineral material from tissue, for example, bone tissue. Incertain embodiments, the demineralized compositions described hereininclude preparations containing less than 5% calcium and preferably lessthan 1% calcium by weight. Partially demineralized bone (e.g.,preparations with greater than 5% calcium by weight but containing lessthan 100% of the original starting amount of calcium) is also consideredwithin the scope of the invention. In some embodiments, demineralizedbone has less than 95% of its original mineral content. Demineralized isintended to encompass such expressions as “substantially demineralized,”“partially demineralized,” and “fully demineralized.”

“Demineralized bone matrix,” as used herein, refers to any materialgenerated by removing mineral material from bone tissue. In preferredembodiments, the DBM compositions as used herein include preparationscontaining less than 5% calcium and preferably less than 1% calcium byweight. Partially demineralized bone (for example, preparations withgreater than 5% calcium by weight but containing less than 100% of theoriginal starting amount of calcium) are also considered within thescope of the invention.

“Osteoconductive,” as used herein, refers to the ability of anon-osteoinductive therapeutic agent to serve as a suitable template ortherapeutic agent along which bone may grow.

“Osteogenic,” as used herein, refers to the ability of an agent,material, or implant to enhance or accelerate the growth of new bonetissue by one or more mechanisms such as osteogenesis, osteoconduction,and/or osteoinduction.

“Osteoimplant,” as used herein, refers to any bone-derived implantprepared in accordance with the embodiments of this invention andtherefore is intended to include expressions such as bone membrane, bonegraft.

“Osteoinductive,” as used herein, refers to the quality of being able torecruit cells from the host that have the potential to stimulate newbone formation. Any material that can induce the formation of ectopicbone in the soft tissue of an animal is considered osteoinductive. Forexample, most osteoinductive materials induce bone formation in athymicrats when assayed according to the method of Edwards et al.,“Osteoinduction of Human Demineralized Bone: Characterization in a RatModel,” Clinical Orthopaedics & Rel. Res., 357:219-228, December 1998,incorporated herein by reference.

“Superficially demineralized,” as used herein, refers to bone-derivedelements possessing at least about 90 weight percent of their originalinorganic mineral content, the expression “partially demineralized” asused herein refers to bone-derived elements possessing from about 8 toabout 90 weight percent of their original inorganic mineral content andthe expression “fully demineralized” as used herein refers to bonecontaining less than 8% of its original mineral context.

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, for example, 5.5 to 10.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

I. Introduction

A delivery system for delivering therapeutic agents or materials to asurgical site is provided. In various embodiments, the delivery systemcomprises an implantable covering, for example a mesh bag, having atleast two compartments configured to receive at least a first and asecond therapeutic agent for delivery to a surgical site. The at leasttwo compartments comprise top and bottom ends and sides defining, inseveral aspects, a cylindrical shape. At least one of the top or bottomends define an opening configured to receive a removable filling memberand having also a closing member. The removable filling member, forexample a funnel, is utilized to fill at least one compartment withautograft material or another therapeutic agent. The covering provides asuperior containment of the therapeutic agent, such as graft material,which helps focus and concentrate materials that provide healing at thesurgical site. In some embodiments, the covering also helps the surgeonperform less invasive procedures, by delivering a contained unit ofgrafting material to the surgical site.

The delivery system described herein provides increased handlingproperties, ability to place grafting material reliably using minimallyinvasive procedures, and improved delivery characteristics such as graftretention compared with other systems. In some embodiments, uponplacement, the covering facilitates transfer of the therapeutic agentand/or materials to the surgical site. In some embodiments, for examplewherein the covering holds graft materials, the covering substantiallyprevents graft migration. The covering may participate in, control, orotherwise adjust, the release of the therapeutic agent from the coveringor penetration of the covering by surrounding materials, such as cellsor tissues.

The delivery system may be used to treat a wide variety of bone or softtissue defects including surgically created or pre-existing (such as bytrauma) defects. On some embodiments, the delivery system may be used totreat contained bony voids or contained defects. Such bony voids arevoids or cavities that have a cortical shell on three sides. In someembodiments, the delivery system may be used to treat critical defects.Generally, critical defects are defects that will not heal spontaneouslyand must be grafted in order to assure healing. In some embodiments, thedelivery system may be used to treat segmental defects. Segmentaldefects are defects in the cortical shaft of a long bone in which asegment is missing. In some embodiments, the delivery system may be usedto treat contained or non-critical defects wherein the delivery systemmay act as a plug to assist healing. Other applications for the deliverysystem are discussed herein and none are intended to be limiting.

Generally, the covering may be at least a two compartment structurecapable of at least partially retaining a therapeutic agent providedtherein until the covering is placed at a surgical site. In someembodiments, the covering may be substantially non-expandable orminimally deformable. In some embodiments, the covering may be atemporary covering wherein the covering is substantially resorbable. Forexample, in some embodiments, the covering may be formed of a materialthat is substantially resorbed within 2 weeks, within 4 weeks, within 12weeks, or within other suitable time frame. Accordingly, in someembodiments a delivery system including the covering may be a temporarydelivery system. The covering may include one or more attachmentmechanisms for retaining the covering at the surgical site. Theattachment mechanism may be a mechanical attachment mechanism, aphysical attachment mechanism, a biological attachment mechanism or achemical attachment mechanism, or may employ combinations of these. Theattachment mechanism may be used to attach the covering to skeletal orsoft tissue proximate the surgical site.

In some embodiments, the covering may be used for containment ofparticulate or morselized materials (the therapeutic agent provided inthe covering), optionally to provide a focus or concentration ofbiological activity. In some embodiments, the covering may be used forcombining DBM particles and/or fibers with various bone graftingmaterials to achieve more effective mixing of these materials andcontain them for delivery at the desired location. In variousembodiments, bone grafting materials include one or more of boneparticles, bone fibers, other osteoinductive or osteoconductivematerials, BMP, antibiotics, or other materials.

In some embodiments, the covering may be used for maintaining materials(the therapeutic agents provided in the covering) in spatial proximityto one another, possibly to provide a synergistic effect upon mixingwith each other. In some embodiments, the covering may be used tocontrol availability of therapeutic agents provided within the coveringto cells and tissues of a surgical site over time. In some embodiments,the covering may be used for delivery through a limited opening, such asin minimally invasive surgery or mini-open access. In some embodiments,the covering may be used to deliver morselized or particulated materials(the therapeutic agent provided in the covering) in pre-measuredamounts. In other embodiments, the therapeutic agent may be liquid orflowable, or combinations of these with particulate, morselized, and/orother materials.

In various embodiments, the covering may contain a therapeutic agentsuch as a graft material. The covering limits, and in some embodimentseliminates, graft migration and maintains graft density. The deliverysystem, with contained therapeutic agent or material, may be configuredto conform to surrounding bony contours or implant space. On someembodiments, the delivery system provides a pathway for healing/cellpenetration and tissue ingrowth. Thus, the covering may facilitatetransfer or diffusion of materials into and out of the covering. Forexample, the covering may facilitate diffusion from the covering of atherapeutic agent provided within the covering or may facilitatediffusion into the covering of materials in the surgical site, such ascells and tissues, into the covering. The covering may be configured topermit diffusion of some materials while substantially preventingdiffusion of other materials. Further, in various embodiments, thecovering may be configured such that diffusion is permitted into or outof certain portions of the covering but not other portions of thecovering. In some embodiments, the covering may merely retain atherapeutic agent at the surgical site.

The covering may have at least two compartments or may have a pluralityof compartments. Thus, in one embodiment, the covering isdual-compartment and comprises first and second compartments. A firsttherapeutic agent may be provided in the first compartment and nomaterial or a second therapeutic agent may be provided in the secondcompartment. The second compartment may be adjacent to, apart from,inside, or surrounding the first compartment. In various embodiments,the at least two compartments are temporarily separated by separatingmembers, for example drawstrings that can be pulled to allow the firstand second therapeutic agents to mix prior to delivery at a surgicalsite.

Materials forming the first compartment and the second compartment maybe the same or may be different. Selection of materials, positioning ofthe compartments, and other factors relating to the first and secondcompartments may be chosen to achieve simultaneous or sequentialdelivery or release of a therapeutic agent or therapeutic agents.

In various aspects, the biological environment for inducing new bonegrowth with DBM particles is optimized by allowing as many hostosteogenic cells or growth factors adjacent to DBM particles. If asufficient amount of proper live cells do not surround the DBMparticles, they could easily be resorbed by macrophages and osteoclastsresulting in little to no new bone formation. The delivery systemsdescribed in the present disclosure include a mesh bag comprisingseparate compartments temporarily separated by drawstrings. Some of thecompartments containing DBM are sealed closed at manufacture and somecompartments can be empty with an opening into which local autograftparticles can be placed. Once the autograft is added to an unfilledcompartment, a flap attached to the empty compartment can be sutureclosed, the drawstrings can be removed by pulling at one end, therebyallowing the DBM particles and autograft particles to be thoroughlymixed inside the mesh bag. A funnel with a clip can be used to fill theempty compartment with autograft particles. In some embodiments, theclip can have a spring that can be temporarily attached to the bag andthe funnel holds open the empty compartment to facilitate its fillingwith autograft particles. Other alternative delivery systems capable ofachieving the thorough mixing of DBM particles and other therapeuticagents are also contemplated.

II. Covering Material

The covering may comprise a structural material and, in someembodiments, a functional material. The structural material may comprisea mesh material, a polymeric material, a substantially solid material,or other material. The functional material may comprise, for example, aradiopaque material, a bacteriocidal material, or other material.

Structural Material Characteristics

In various embodiments, in accordance with the specific application forwhich the covering is being used, the covering may be rigid, may beflexible, may be non-elastic, or may be elastic. The covering materialmay be braided, woven, non-woven shape memory, particulate, threaded,porous, non-porous, or substantially solid. While the term “structural”is used to describe the material forming the main structure of thecovering, it is to be appreciated that this is not intended to implythat the covering need have structural or load-bearing characteristics.

The covering may participate in, control, facilitate, prevent, orotherwise adjust the release of the therapeutic agent. For example, thecovering may act as a selectively permeable membrane and/or may beporous, with the level of porosity being related to the nature of thetherapeutic agents inside the covering. Thus, the material for andconfiguration of the covering may be selected or adjusted based ondesired release characteristics. Specific properties of the structuralmaterial that may be adjusted include thickness, permeability, porosity,strength, flexibility, elasticity, and others. It is to be appreciatedthat some of these properties may depend on others. For example, thethickness and porosity of the material may contribute to its strength,flexibility, and elasticity. In some embodiments, the covering may bemade of a squishy, moldable, sticky, and/or tacky material to facilitateplacement and packing of the covering.

In some embodiments, the covering may be porous to fluid and/or cells,may be biocompatible, and may be resistant to rupture (including shouldthe therapeutic agent provided therein swell). In some embodiments, thecovering with the therapeutic agent provided therein may beload-bearing. The covering may be resorbable or non-resorbable. Thecovering may provide increased handling properties, may have irrigationresistance, may have material retention characteristics, and/or maysupport cellular penetration. Flexibility of the covering may beselected to suit particular applications. In some applications, it maybe desirable to have a flexible covering.

If the covering is made from a resorbable material, the coveringdegrades and disappears after a period of time. The covering thus may beconsidered a temporary covering. If the covering is not made of aresorbable material, the covering remains in the body. Tissue ingrowthmay occur to bind the host tissue to the therapeutic agent providedwithin the covering. Tissue ingrowth through and around the covering,between the host tissue and the therapeutic agent provided within thecovering, may be promoted via openings in the covering.

In various embodiments, the covering may comprise a porous material or amesh material. The size of the pores of the covering may be designed topermit cellular infiltration (approximately several microns to severalmillimeters), but may also be designed specifically to exclude cellsfrom the inside of the covering (e.g. approximately 0.45 microns) andonly allow diffusion of small molecules (proteins and hormones). Thus,the covering may act to control access to the interior of the deliverysystem by cells. U.S. Patent Application Publication No. 2005/0283255for Tissue-Derived Mesh for Orthopedic Regeneration describes suitablemanners for forming a mesh for use with a covering as provided hereinand is herein incorporated by reference in its entirety.

The covering may be formed of a resorbable or nonresorbable, natural orsynthetic, biocompatible material. In some embodiments, more than onematerial may be used, including as multiple layers. For example, in anembodiment comprising two compartments, one or more materials may beused for the first compartment and a different material or materials maybe used for the second compartment. For example, one compartment orportions thereof may be made of material or materials that provide adesired property or properties relative to other compartments orportions thereof, such as increased or decreased resorbability orstiffness, or the different compartments or portions thereof may beimparted with different drug delivery properties. Alternatively, allcompartments may comprise the same material or mixtures of materials.Where the characteristics of the material are varied betweencompartments or over the surface of a single compartment, the pores ofthe first compartment or portion thereof may be larger than the pores ofthe second compartment.

The covering may comprise any suitable structure for delivering atherapeutic agent in vivo. Thus, as described, the covering may comprisea mesh. In other embodiments, the covering may comprise a polymericstructure with a chamber provided therein. The chamber may be filledwith a therapeutic agent for delivering in vivo, such as autograft,demineralized bone matrix, or others disclosed herein.

In embodiments comprising more than one compartment, characteristics ofthe covering material may be varied between compartments. Generally, theporosity, flexibility, strength, or any other characteristic of onecompartment may vary from that characteristic of the other compartment.Further, characteristics of the covering may vary at different positionsof the covering regardless of compartmental configuration of thecovering.

In some embodiments, the covering may expand when placed in the body.Expansion can be provided in at least two ways: the covering may becompressed such that the covering expands when placed in the body or thecovering may be made of a material that expands when it comes in contactwith water or other bodily fluids, either by way of liquid absorption,or by stretching when the materials inside it absorb liquid andthemselves expand. In some embodiments, the covering may comprise ashape memory material such as copper-zinc aluminum-nickel alloy,copper-aluminum-nickel alloy, and nickel-titanium (NiTi) alloy.Reinforcing materials such as cortical bone, calcium phosphates, etc.may be incorporated into the structure of the covering to reinforce it.In other embodiments, the covering may be substantially non-expandableor minimally deformable.

The covering may be configured for specific compressive strength andrigidity by adjusting density and resorption time of the covering. Insome embodiments, a coating may be provided over the covering. Forexample, the coating may be a compound of poly-L-lactide, ofpolyglycolic acid, or their polymers, or polyhydroxyalkanoates(polyhydroxybutyrates and polyhydroxyvalerates and copolymers). Thecoating may be selected such that it has a resorption time wherein it isresorbed by the body and the material within the covering is permittedto exit through openings in the covering.

A covering according to an aspect of the present application maycomprise at least one of bioerodible polymers, bioabsorbable polymers,biodegradable biopolymers, synthetic polymers, copolymers and copolymerblends and combinations thereof. Exemplary materials may includebiopolymers and synthetic polymers such as human skin, human hair, bonesheets, collagen, fat, thin cross-linked sheets containing fibers and/orfibers and chips, degradable sheets made from polyethylene glycol (PEG),chitosan sheets, alginate sheets, cellulose sheets, hyaluronic acidsheet, as well as copolymer blends of poly (lactide-co-glycolide) PLGA.

Advantageously, a covering according to an aspect of the presentapplication utilizes polymer materials, which provide increased shelflife and further impart and/or improve moisture and/or radiationresistance. Accordingly, a covering provides improved stability, isresistant to environmental degradation, and provides increaseddurability to e.g., sterilization procedures.

Exemplary Covering Materials

Polymeric material (for example, see U.S. Pat. Nos. 6,696,073,6,478,825, 6,440,444, and 6,294,187 and U.S. Patent Publications Nos.2006/0216323 and 2005/0251267, all herein incorporated by reference intheir entirety); woven material and braided material (for example, seeU.S. Patent Publication No. 2005/0283255, herein incorporated byreference in its entirety); non-woven materials; shape memory material;porous materials; and non-porous materials may be used. In someembodiments, outer particles may be used to contain inner particles;particles may be attached to threads of material, and/or porosity may beadded to mesh fibers. In some embodiments, materials may be used forportions of the covering, such as for a compartment of the covering,that are substantially impenetrable.

In some embodiments, the covering may comprise a mesh material. Suitablemesh materials include natural materials, synthetic polymeric resorbablematerials, synthetic polymeric non-resorbable materials, and othermaterials. Natural mesh materials include silk, extracellular matrix(such as DBM, collagen, ligament, tendon tissue, or other),silk-elastin, elastin, collagen, and cellulose. Synthetic polymericresorbable materials include poly(lactic acid) (PLA), poly(glycolicacid) (PGA), poly(lactic acid-glycolic acid) (PLGA), polydioxanone, PVA,polyurethanes, polycarbonates, polyhydroxyalkanoates(polyhydroxybutyrates and polyhydroxyvalerates and copolymers),polysaccharides, polyhydroxyalkanoates polyglycolide-co-caprolactone,polyethylene oxide, polypropylene oxide, polyglycolide-co-trimethylenecarbonate, poly(lactic-co-glycolic acid), and others. Other suitablematerials include carbon fiber, metal fiber, polyertheretherketones,non-resorbable polyurethanes, polyethers of all types, polyethyleneterephthalte, polyethylene, polypropylene, Teflon, and various othermeshes. In other embodiments, the covering may comprise non-wovenmaterial such as spun cocoon or shape memory materials having a coilshape or shape memory alloys. Alternatively, any of these materials maybe used in a non-mesh form.

Generally, the covering may be formed of any natural or syntheticstructure (tissue, protein, carbohydrate) that can be used to form acovering configuration. Thus, the covering may be formed of a polymer(such as polyalkylenes, for example, polyethylenes, polypropylenes),polyamides, polyesters, poly(glaxanone), poly(orthoesters),poly(pyrolicacid), poly(phosphazenes), polycarbonate, otherbioabsorbable polymer such as Dacron or other known surgical plastics, anatural biologically derived material such as collagen, gelatin,chitosan, alginate, a ceramic (with bone-growth enhancers,hydroxyapatite), PEEK (polyether-etherketone), dessicated biodegradablematerial, metal, composite materials, a biocompatible textile (forexample, cotton, silk, linen), extracellular matrix components, tissues,or composites of synthetic and natural materials, or other. Variouscollagen materials can be used, alone or in combination with othermaterials, including collagen sutures and threads. Some examples includepolymer or collagen threads woven, or knitted, into a mesh. Othersuitable materials include thin polymer sheets molded in the presence ofa porogen and having underwent leaching; polymer sheets or naturallyderived sheets such as fascia and other collagen materials, smallintestinal submucosa, or urinary bladder epithelium, the sheets beingpunctured to introduce porosity; specific shapes printed using availableor future printing technologies; naturally secreted materials such asbacterial cellulose grown within specific molds.

In some embodiments, mesh fibers may be treated to impart porosity tothe fibers. This may be done, for example, to PLA, PLGA, PGA, and otherfibers. One suitable method for treating the mesh fibers comprisessupercritical carbon dioxide treatment to partially solubilize theparticles. This treatment may further be carried out for viralinactivation. Another suitable method for treating the mesh fiberscomprises explosive decompression. Explosive decompression generatesporosity and leads to controlled permeability. The mesh material furthermay be loaded with cells, growth factors, or bioactive agents.

In further embodiments, fibers of a mesh material may be treated such asby having particles adhered thereto. The particles may be, for example,bone particles. Thus, in one embodiment, the covering may comprise aplurality of threads formed into a fabric. The threads may haveparticles adhered thereto. For example, the threads may have particlesstrung on the thread. In an alternative embodiment, the covering may beformed of a material and the material may be coated with particles.

In yet other embodiments, the covering may comprise a non-porousmaterial, which may be permeable. A non-porous material may be used forlater (or delayed) delivery of a therapeutic agent provided therein.Such therapeutic agent may comprise, for example, cells, growth factors,or bone morphogenetic proteins. Accordingly, in one embodiment, adelivery system for delayed delivery of cells, growth factors, or bonemorphogenetic proteins is provided comprising a non-porous covering.

While certain embodiments are described with respect to having meshcharacteristics, it is to be appreciated that not all embodiments mayhave such mesh characteristics. Further, the material used for thecovering and its characteristics may be selected for specificapplications. For example, in some embodiments, the covering may beformed of a resorbable material, such as formed as a resorbablecontainer or capsule. Such resorbable material may be useful indelivering, for example, antibiotic to a site by an outer resorbablematerial, and then gradually exposing inner graft material after theinfection is cleared. In such embodiments, the delivery system comprisesa temporary delivery system.

Functional Material Characteristics

The covering material may have functional characteristics.Alternatively, other materials having functional characteristics may beincorporated into the covering. Functional characteristics may includeradiopacity, bacteriocidity, source for released materials, tackiness.Such characteristics may be imparted substantially throughout thecovering or at only certain positions or portions of the covering.

Suitable radiopaque materials include, for example, ceramics,mineralized bone, ceramics/calcium phosphates/calcium sulfates, metalparticles, fibers, iodinated polymer or mixtures thereof. Othertechniques for incorporating a biocompatible metal or metal salt into apolymer to increase radiopacity of the polymer may also be used.Suitable bacteriocidal materials may include, for example, tracemetallic elements. In some embodiments, trace metallic elements may alsoencourage bone growth.

Functional material, such as radiopaque markers, may be provided at oneor more locations on the covering or may be provided substantiallythroughout the covering. Thus, for example, in a tubular covering, aradiopaque marker may be provided at a tip of the tubular covering. Suchmarker may facilitate placement of the covering. Radiopaque materialsmay be incorporated into the covering and/or into the therapeutic agentfor delivery by the covering. Further, radiopaque materials may beprovided at only some locations on the covering such that visualizationof those locations provides indication of the orientation of thecovering in vivo.

The covering itself may be designed to release materials duringdegradation of the covering material. Thus, bone morphogenic proteins(BMPs), growth factors, antibiotics, angiogenesis promoting materials(discussed more fully below), bioactive agents (discussed more fullybelow), or other actively releasing materials may be incorporated intothe covering material such that as the covering material is degraded inthe body, the actively releasing material is released. For example, anactively releasing material may be incorporated into a biodegradablepolymer covering such as one manufactured of a biodegradable polyestersuch as poly(lactic acid) (PLA), poly(glycolic acid) (PGA),poly(lactic-co-glycolic acid) (PLGA), or polyhydroxyalkanoates(polyhydroxybutyrates and polyhydroxyvalerates and copolymers). In someembodiments, poly(ethylene glycol) (PEG) may be incorporated into thebiodegradable polyester to add hydrophilic and other physico-chemicalproperties to enhance drug delivery. In some embodiments, composites ofallograft bone and biodegradable polymers (for example, PLEXUR™ productsavailable from Medtronic) may be used in the covering.

In some embodiments, the covering may comprise a material that becomestacky upon wetting. Such material may be, for example, a protein orgelatin based material. Tissue adhesives, including mussel adhesiveproteins and cryanocrylates, may be used to impart tackiness to thecovering. In further examples, alginate or chitosan material may be usedto impart tackiness to the covering. In further embodiments, an adhesivetherapeutic agent or material may be placed on a portion of the coveringor in a particular region of the covering to anchor that portion orregion of the covering in place at an implant site.

In one embodiment of a covering comprising two compartments, first andsecond materials may be used for the first and second compartments,respectively. The first material may release or expose a growth factoraccording to a first rate and the second material may release a growthfactor according to a second rate. Further, the growth factors releasedby the first and second compartments may be the same or may bedifferent. For example, an angiogenic growth factor may be provided withthe first compartment and an osteoinductive growth factor may beprovided with the second compartment.

Mesh Formulation

Any suitable technique may be used for forming a material for thecovering. Generally, the material may be formed as a substantially solidmaterial, as a sheet, as a mesh, or in other configuration. In someembodiments, the material may be a textile type material. Thus, forexample, the material may be formed using a textile approach such as beweaving, rug making, knitting. Such formation may be by a mechanical orindustrial method. In another embodiment, a substantially solid sheetmay be formed and may be treated to assume a configuration penetrable bycells, fluids, and proteins. For example, the sheet may be perforated,may be expanded to create openings, or other. Also, it would beperfectly suitable to take a thin sheet of the covering material, and toperforate it, expand it to create openings, or otherwise make itpenetrable by cells, fluids and proteins.

In one embodiment, elongated bone-derived particles or fragments ofsmall intestinal submucosa may be combined longitudinally into threesmall bundles, each having, for example, from about 1 to about 3 tissueparticles. The three bundles may then be braided. Various methods ofbraiding and types of braids any of which may be useful in producing thematerial of the invention herein are also described, for example, byShaw, KNOTS—Useful & Ornamental, Bonanza Books, New York (1983),incorporated herein by reference. The ends of the braided tissue-derivedparticles may then be glued together using a fixation agent to preventtheir unraveling, or they may be held together with a biocompatiblepolymer or metal band.

In an alternative embodiment, bone-derived particles are combined with asolvent to form a material. Exemplary solvents include water, loweralkanols, ketones, and ethers and mixtures of any of these or othermaterials. The material may then be extruded at an appropriatetemperature and pressure to create a thread. Threads may also beproduced by spinning, drawing, rolling, solvent-extruding, cutting orlaser cutting from a sheet or bar stock. The material may alternativelybe cast or molded into a solid sheet or bar stock and then cut into thinthreads. These may be used immediately or woven into a mesh.Alternatively or in addition, they may be spliced, wrapped, plied,cabled, braided, woven, or some combination of these. The material maybe shaped by thermal or chemical bonding, or both. In one embodiment, aportion of the solvent is removed from the material before extrusion.

Alternatively or in addition, the material may be cast as a slurry,extruded, or molded. A variety of materials processing methods will bewell known to those skilled in the art. For example, the material may besolvent cast using a press such as a Carver press to spread the materialinto a film. Solvent evaporation will yield a porous film.Alternatively, the material may be compression molded into a film. Themesh size or porosity of the film will depend on the thickness of thefilm and the viscosity of the precursor and can be easily manipulated byone skilled in the art. Where elongated particles are used in anextruded aggregate, they will tend to be aligned roughly parallel to oneanother.

In an alternative embodiment, a thread of a biocompatible natural orsynthetic material, for example, polylactide or collagen, may be coatedwith tissue-derived or other elements, for example, by dubbing. Forexample, a polymer fiber may be coated with an adhesive, for example,lecithin, and bone particles or other osteoconductive or osteoinductivefibrils allowed to adhere to the thread. The thread may then be twistedon itself or with a second or a plurality of similarly treated threads.Alternatively or in addition, the threads may be braided. The adhesivemay be a lipid that is waxy at room temperature, for example, a di- ortri-glyceride that is solid at room temperature. Alternatively or inaddition, the adhesive may be a phosphocholine or phosphatidylcholine.In some embodiments, the adhesive is a material that binds both thethread and the material that is used to coat the thread (e.g., boneparticles) but that does not degrade either. Non-aqueous adhesives mayimprove the stability of the final aggregate as compared to aqueousadhesives.

Suitable fibers may be formed utilizing well known techniques, includingbraiding, plying, knitting, weaving, felting, that are applied toprocessing natural fibers, for example, cotton, silk, and syntheticfibers made from synthetic bioabsorbable polymers, such aspoly(glycolide) and poly(lactic acid), nylon, cellulose acetate. See,Mohamed, American Scientist, 78: 530-541 (1990). In some embodiments,collagen thread is wound onto cylindrical stainless steel spools. Thespools are then mounted onto the braiding carousel, and the collagenthread is then assembled in accordance with the instructions providedwith the braiding machine. In one particular run, a braid was preparedof four collagen threads, which consisted of two threads ofnon-crosslinked collagen and two threads of crosslinked collagen. Oneskilled in the art will recognize that these techniques may be appliedto the other fibrous materials described herein.

Fibers and more evenly dimensioned particles may also be plied intoyarns using the same methods and same machinery known to those skilledin the art in plying threads made out of other material, such as cotton,polyester. Four collagen threads were twisted together. Three of theresultant 4-ply strands were then twisted together in the oppositedirection, and then 5 of the resultant 12 ply strands were twisted inthe opposite direction.

Elongated materials including multistranded materials, for examplebraids, plied yams, cables, may be knitted into tubular or flat fabricsby using techniques known to those skilled in the art of producingfabrics manufactured from other types of threads. Various biologicallyactive therapeutic agents can be incorporated in, or associated with,the braided, knitted, or woven materials. Particles and fibers andmaterials of these (including multistranded materials) may alternativelyor additionally be assembled into a material by non-woven methods suchas laying, needle-punching, and hooking (as for a rug). For example, athread may be attached to another thread or a pressed film.

Regardless of the assembly method, the material shape, mesh size, cablethickness, and other structural characteristics, such as architecture,may be customized for the desired application. For example, where a twodimensional aggregate is used to retain a thixotropic material within agap, a tight weave is preferred to prevent leakage. To optimize cell orfluid migration through the mesh, the pore size may be optimized for theviscosity and surface tension of the fluid or the size of the cells. Forexample, pore sizes on the order of approximately 100-200 μm may be usedif cells are to migrate through the mesh. Mesh size may be controlled byphysically weaving strands of the material by controlling the ratio ofsolvent to solids in a precursor material.

Cells may be seeded onto the material, or contained within it. In oneembodiment, cells may be encapsulated in a matrix such as alginate orcollagen gel and the capsules placed on the material. Seeded materialsgenerally do not need to be incubated for long periods of time insolutions that could partially dissolve the binding agent. Instead, thecapsules may be placed on the material or covering shortly beforeimplantation. In another embodiment, cells are simply mixed with a gelwhich is then combined with the material. Alternatively, a material orcovering may be cultured with cells before implantation. In oneembodiment, thicker materials are used for culturing to increasemechanical integrity during implantation. Any class of cells, includingconnective tissue cells, organ cells, muscle cells, nerve cells, andstem cells, may be seeded onto the implant. In an exemplary embodiment,connective tissue cells such as osteoblasts, osteoclasts, fibroblasts,tenocytes, chondrocytes, and ligament cells and partially differentiatedstem cells such as mesenchymal stem cells and bone marrow stromal cellsare employed.

III. Covering Configuration or Form

The shape, configuration, or form of the covering may be selected forparticular applications. Such shape and configuration may include, forexample, the basic shape of the covering (for example, a cylinder or abag), whether the covering has a single or a plurality of compartments,and whether the covering includes attachment mechanisms. The covering(or delivery system) may be configured to conform to surrounding bonycontours of the space in which it is placed.

Form

In various embodiments, the covering may be formed of as a mesh and maycomprise a woven material. The woven material may have varying degreesof permeability. It may be permeable, semi-permeable, or non-permeable.Permeability may be with respect to cells, to liquids, to proteins, togrowth factors, to bone morphogenetic proteins, or other. In furtherembodiments, the material may be braided.

In alternative embodiments, the covering may comprise a substantiallysolid structure, such as a polymer structure with a chamber, or a spuncocoon.

Shape

The covering may have any suitable configuration. For example, thecovering may be formed as a ring, a cylinder, a cage, a rectangularshape, a mesh, a suture-like wrap, a continuous tube, or otherconfiguration. In specific embodiments, the covering may be formed as athin tube designed to be inserted through catheters or an introducertube, a rectangular shape designed to fit adjacent to spinal processesfor posterolateral spine fusion, a cube like structure designed to fitbetween vertebral bodies or within cages for interbody spinal fusion, atube-like shape where the ends are designed to be fitted onto nonunionlong bone defects, relatively flat shapes designed to fill cranial ormaxillofacial defects, rectangular structures designed for osteochondraldefects, structures pre-shaped to fit around various implants (forexample, dental, doughnut with hole for dental implants), or relativelyelastic ring-like structures that will stretch and then conform toshapes (for example, rubber band fitted around processes). In anembodiment wherein the covering is formed as a cage, the cage maycomprise a plurality of crossed filaments which define between them aseries of openings for tissue ingrowth. Any of these shapes may be usedfor a covering comprising a plurality of compartments. For example, in atubular embodiment, the tube may be formed into a plurality ofcompartments by tying a cord around the tube at one or more points, orby other suitable mechanism such as crimping, twisting, knotting,stapling, sewing, or other. The configuration of the covering may bedetermined by the therapeutic agent to be provided within the covering.For example, if the therapeutic agent to be contained comprises fibers,the covering may be formed as strings or sutures that are wrapped aroundthe fibers.

In certain embodiments, a bone void can be filled. A compartment withinthe covering material can be at least partially filled with a bonerepair substance. In various embodiments, at least partially filled asused herein, can mean that a percentage of the volume of a compartment(or covering material, as applicable) is at least 70% occupied, at least75% occupied, at least 80% occupied, at least 85% occupied, at least 90%occupied, at least 95% occupied, or 100% occupied. The covering materialcan be inserted into an opening in the defect until the defect issubstantially filled. In various embodiments, a substantially filled asused herein can mean that a percentage of the volume of a defect (orcovering material, as applicable) is at least 70% occupied, at least 75%occupied, at least 80% occupied, at least 85% occupied, at least 90%occupied, at least 95% occupied, or 100% occupied. The excess materialextending beyond the surface of the bone if the bone were without thedefect can then be removed, or at least partially removed such that theopening of the defect is flush with the uninjured bone surface.

In some embodiments, the covering may be labeled. Such labeling may bedone in any suitable manner and at any suitable location on thecovering. In some embodiments, labeling may be done by using a silkscreen printing, using an altered weaving or knotting pattern, by usingdifferent colored threads, or other. The labeling may indicateinformation regarding the covering. Such information might include partnumber, donor id number, number, lettering or wording indicating orderof use in the procedure or implant size.

Compartments

Osteogenic material delivery systems in accordance with embodimentsdiscussed in this disclosure are depicted in FIGS. 1, 2 and 3. In someembodiments, as shown in FIG. 1, delivery system 100 comprises covering102 having an elongated containment portion 104 separated into threecompartments 106, 108 and 110 for housing therapeutic agents fordelivery to a surgical site. Situated side by side, compartments 106,108 and 110 are separated from each other by first and second separationmembers 116, 118. Elongated containment portion 104 also includes alength, width and height or cross section which may vary depending onthe application for covering. The cross section can be tubular orcylindrical and in alternative embodiments, any cross-sectional shape,such as a generally circular, oval, rectangular, generally square,generally star, or any other suitable shape may be used. In theembodiments shown in FIGS. 1, 2, and 3 the coverings 102, 202 and 302comprise a mesh material and the delivery systems 100, 200 and 300 canbe a mesh bag. Within these coverings or mesh bags, there is provided aparticulated therapeutic agent such as milled bone or DBMparticles/fibers, wherein the ratio of DBM fibers to DBM chips is about30:60.

Containment portion 104 also contains top and bottom ends 112, 114. Asfurther depicted in FIG. 1, in some embodiments, compartments 106 and110 are enclosed and there is provided a particulate therapeutic agentsuch a milled bone or DBM particles/fibers. Compartment 108 can be leftempty or it can be partially or completely filled with autograftparticles. In one embodiment, at top end 112, compartment 108 defines anopening 120 which can be sealed closed by a closing member 122. Closingmember 122 can be a flap sealable by suturing, heating, using adhesives,solvent treatment, knotting, using interference, friction fits or anyother means.

In various embodiments, separation members 116 and 118 temporarilyseparate compartments 106 and 110 from 108. While compartments 106 and110 can contain DBM and are sealed closed, compartment 108 can be empty.At opening 120, compartment 108 is configured to receive a fillingmember 400, which, as illustrated in FIG. 4, can be a funnel.

In various embodiments, the covering may be configured to facilitateplacement of graft material therein. For example, in FIG. 1, temporaryseparation members 116 and 118 can be completely removed to allow formixing of the materials present in all three compartments prior toinsertion at a surgical site. In some aspects, compartment 108 can beleft unfilled or it can be partially or completely filled either withautograft and/or growth factors thereby increasing the exposure of DBMparticles/fibers to osteogenic cells and allowing the DBM cytokines tosignal the autologous osteogenic cells to begin forming new bone toboost the osteoactivity of the weakly osteoinductive DBM already presentin covering 102.

In other aspects, as shown in FIG. 2, delivery system 200 contains acovering 202 having temporary separation members or pull strings 216 and218 which can be partially pulled to create three cylindrically shapedside by side compartments 206, 208 and 210 shown as generally circularcompartments in a top view. In some embodiments, as illustrated in FIG.2, compartment 208 is left empty, but upon pulling strings 216, 218, thevolume of covering 202 can decrease or shrink (e.g., reduce in size, ormake compact), allowing the surgeon flexibility to fashion covering 202as required for a specific surgical site. In other aspects, compartment208 can be filled with autograft or other desirable additives.

With further reference to FIG. 1, as pull strings 116 and 118 areremoved, the bone graft material in compartment 108 is forced to mixwith, surround and coat the DBM particles/fibers so that bone formationcan be induced throughout the graft rather than just along the surfaceof the DBM containing mesh bag. This is allows live cells and/or growthfactors to contact the DBM particles and induce bone growth throughoutthe complete graft rather than just along the surface of the DBMcontaining mesh bag or covering.

FIG. 3 is a side view of another embodiment of a delivery system 300having a covering 302 containing two side by side compartments 306 and308 separated by separation member 316, in this embodiment a pullstring. Compartment 308 can be unfilled or partially filled either asmanufactured or as subsequently filled at a surgical site. Compartment308 is sealed closed at bottom end 314 but forms an opening 320 at topend 312. After filling compartment 308, opening 320 can be sealed withclosing member 322, which, in one aspect can be a flap. Opening 320 isconfigured to receive filling member 400 as illustrated in FIG. 4.Opening 320 defines a mating surface 324 which is configured to receivemating surface 454 defined by opening 453 of filling member 400.

FIG. 4 depicts a side view of filling member 400, which in some aspects,is a funnel. The funnel has a head portion 450 and a neck portion 452defining an opening 453 and a mating surface 454 configured to mate withmating surface 324 of compartment 308 or mating surface 124 ofcompartment 108 of covering 102 depicted in FIG. 1. Generally, it iscontemplated that circumferences 456 and 458 are sufficient in size toenable funnel 400 to receive allograft chips and other graft material toallow for the filling of covering compartment 108 of covering 102 orcompartment 308 of covering 302 either by gravity or with the help of aplunger. Additionally, it is contemplated that the head and neck offunnel 400, both include wider or narrower funnel shape configurationsas would generally occur to one skilled in the art to perform its loadassisting function. Filling member 400 also comprises an attachmentmember 460. In some embodiments, attachment member 460 can be a cliphaving a spring 462, which allows funnel 400 to be temporarily attachedto the mesh bag. Other attachment members such as friction orinterference fittings are also contemplated.

In other embodiments, the filling member utilized to fill emptycompartments can be a spoon or a syringe or any other means that canadequately perform a compartment loading function. In some embodiments,the filling member (e.g., funnel) can contain channels for suturing thefilling member to the cover (e.g., bag). After the covering is filledwith material, the suture can be cut and the filling member removed.

In the embodiments shown in FIGS. 1 and 3 both ends 112 and 114, 312 and314, or sides 113 and 115, 313 and 315, respectively can be sealedeither self sealed or sealed by heat, adhesion or stitches. One or bothends or sides may contain an attachment or coupling mechanism (notshown) to attach the covering to skeletal or soft tissue proximate to asurgical site. Any suitable attachment mechanism can be used, such as atab, loop, tack or other structure adapted for attachment at the site.Also, for example, a covering may include a hook-and-eye (Velcro)portion.

In various embodiments, the materials for each compartment may havedifferent release profiles, different porosities, and other differentcharacteristics. Selection of materials, positioning of thecompartments, and other factors relating to the first, second or thirdcompartments may be chosen to achieve simultaneous or sequentialdelivery or release of a therapeutic agent or therapeutic agents. Forexample, a first therapeutic agent may be provided in the firstcompartment, a second therapeutic agent may be provided in the secondcompartment and a third therapeutic agent may be provided in the thirdcompartment. In some embodiments, an osteoinductive therapeutic agentmay be placed in a compartment generally adjacent tissue being treatedas implanted and an osteoconductive therapeutic agent may be placed in acompartment not adjacent tissue being treated. Release rates for thematerials provided in a first compartment, and second compartment may bedifferent from each other and from the material placed in a thirdcompartment. In some embodiments as illustrated in FIGS. 1 to 3, atleast one of the compartments may be unfilled at the time of surgery andautograft or other material may be provided therein in the operatingroom or at the surgical site.

As in embodiments illustrated in FIGS. 1, 2 and 3, the materials foreach compartment shown in these figures may have different releaseprofiles, different porosities, and other different characteristics.Selection of materials, positioning of the compartments, and otherfactors relating to the first, second or third compartments may bechosen to achieve simultaneous or sequential delivery or release of atherapeutic agent or therapeutic agents. For example, a firsttherapeutic agent may be provided in the first compartment, a secondtherapeutic agent may be provided in the second compartment and a thirdtherapeutic agent may be provided in the third compartment.

For multi-compartment coverings, the covering may be closed afterfilling the compartments with the desired therapeutic agents. Further,the covering may be left substantially open with one or more unsealedends. Accordingly, the covering may be provided in an unfilled, unsealedstate. After a therapeutic agent for delivery is placed in the covering,the covering may be permanently or temporarily closed. Permanent closuremay be, for example, by heat sealing, stitching, adhesion, or othermethods. Temporary closure may be by tying, fold lock, or cinching. Atemporarily closed covering can be opened without damaging to thecovering during surgical implantation to add or remove therapeuticagents in the covering.

In some embodiments, at least one but not all of the compartments may beweight-bearing. In other embodiments, all of the compartments may beweight-bearing.

In one embodiment, the covering may comprise a penetrable material at afirst compartment configured for placement adjacent bone and asubstantially impenetrable material at a second compartment configuredfor placement adjacent soft tissue. Alternatively, the material of thecompartments may have substantially identical characteristics. Thecovering then can be positioned in any desirable manner. By way ofexample only, a covering may have a porous surface that is positionedadjacent bone, and a separate or opposite surface that has a generallyimpenetrable surface that is positioned adjacent soft tissue.Alternatively, a covering may have one compartment that comprises aporous material, and a second compartment that comprises a substantiallyimpenetrable material.

Attachment Mechanisms

The covering may be implanted directly at, near or in the bone defect oroptionally be configured with structures to permit attachment at thesurgical site, such as to skeletal tissue or to soft tissue structures,or for attachment to other coverings, or for attachment to adjacentimplantable medical devices or products (such as a rod or screw orcross-brace of a pedicle screw fixation system, a hip prosthesis, a boneplate, and the like). Generally, the attachment mechanism may be used toretain the covering at the surgical site and any mechanisms capable ofdoing so may be used. The attachment may be to bone or to adjacenttissues such as muscle, tendon, or ligament. In some embodiments, theattachment mechanism can be made from a biodegradable polymer that isthe same or different material than the covering.

Where the covering retains a bone graft substance, the covering may beheld in a relatively stable position relative to bone (or relative tothe surgical site or surgical defect) to promote bone growth.Accordingly, in some embodiments, the delivery system may be suitablefor assisting in attaching tendons, artificial tendons, or ligaments tobone or other structure.

The bone or soft tissue to which the covering is attached may beprepared for receiving the attachment mechanism(s). For example, inspinal applications, slots or perforations may be provided in posteriorelements such as transverse processes, spinous processes, or other boneor tissue to receive the attachment mechanism.

Any suitable attachment mechanism may be used, including mechanical,physical, chemical, and biological attachment mechanisms. The attachmentmechanism may be provided at an end of the covering, centrally in or onthe covering, generally in or on the body of the covering, or anycombinations of these. When an attachment mechanism is used to couplefirst and second coverings to one another, such attachment or couplingmay be done pre-implantation or post-implantation. In post-implantationembodiments, the coupling may be done by inserting first and secondcoverings through an opening into a space and coupling the coveringswithin the space. In some embodiments, the covering may be provided withattachment mechanisms to facilitate suturing or other attachment of thecovering in vivo.

In some embodiments, a covering may include an area for receipt of anattachment mechanism. For example, a covering may include a tab forreceipt of a screw. In other embodiments, an attachment mechanism mayinterface with any portion of the covering. For example, a screwattachment mechanism may be threaded through a covering at any location,including central to a containment area of the covering. In someembodiments, a screw attachment mechanism may be threaded through thecovering and the substance provided in the containment area of thecovering.

A further method of attachment may comprise suturing or otherwiseattaching the covering to a tether, anchor, or screw embedded in a bonystructure, e.g. a pedicle screw of a spinal stabilization system. Suchscrew, anchor, or tether may pass through the covering and its containedcontents to provide fixation, or through a tab at a margin of thecovering, or through other structure of the covering.

Chemical attachment mechanisms may comprise, for example, a bioadhesiveor glue, cement, tape, tissue adhesives, or similar mechanism. Chemicalattachment mechanisms may further comprise mechanisms that facilitatecross-linking In further embodiments, attachment mechanisms such ascrimping, welding, soldering, or brazing may be used. For example,tissue welding may be used. Further, attachment may be achieved viafriction.

Suitable adhesives for use may include, for example, cyanoacrylates(such as histoacryl, B Braun, which is n-Butyl-2 Cyanoacrylate; orDermabond, which is 2-octylcyanoacrylate); epoxy-based compounds, dentalresin sealants, dental resin cements, glass ionomer cements, polymethylmethacrylate, gelatin-resorcinol-formaldehyde glues, collagen-basedglues, inorganic bonding agents such as zinc phosphate, magnesiumphosphate or other phosphate-based cements, zinc carboxylate, L-DOPA(3,4-dihydroxy-L-phenylalanine), proteins, carbohydrates, glycoproteins,mucopolysaccharides, other polysaccharides, hydrogels, protein-basedbinders such as fibrin glues and mussel-derived adhesive proteins, andany other suitable substance. Adhesives may be selected for use based ontheir bonding time; e.g., in some circumstances, a temporary adhesivemay be desirable, for example, for fixation during the surgicalprocedure and for a limited time thereafter, while in othercircumstances a permanent adhesive may be desired. Where the compartmentis made of a material that is resorbable, the adhesive can be selectedthat would adhere for about as long as the material is present in thebody. In some embodiments, the covering material may be treated to formchemical linkages between the covering and adjacent tissue, whether boneor soft tissue.

In some embodiments, biological attachment may be via mechanisms thatpromote tissue ingrowth such as by a porous coating or ahydroxyapatite-tricalcium phosphate (HA/TCP) coating. Generally,hydroxyapatite bonds by biological effects of new tissue formation.Porous ingrowth surfaces, such as titanium alloy materials in a beadedcoating or tantalum porous metal or trabecular metal may be used andfacilitate attachment at least by encouraging bone to grow through theporous implant surface. These mechanisms may be referred to asbiological attachment mechanisms.

In some embodiments, the covering can comprise edges having polymersthat are more hydrophilic than the polymers in other areas of thecovering (e.g., body). In this embodiment, the covering, when implanted,will draw bodily fluid to this area more so than in other areas and thiswill cause the edges of the covering to expand and anchor the coveringat, near or in the defect site. Alternatively, the body of the coveringcan have polymers that are more hydrophilic than the polymers in theedges of the covering. In this embodiment, the covering, when implanted,will draw bodily fluid to the body area more so than the edges and thiswill cause the body of the covering to expand and anchor the coveringat, near or in the defect site.

Generally, any combination of mechanical, physical, chemical, orbiological attachment mechanisms may be used.

Any of the various attachment mechanisms may be provided as part of thecovering or may be supplied separately. In various embodiments, theattachment mechanisms may be integral to the covering. Alternatively,the attachment mechanisms may be secured to the covering, for example,by stitching, welding, crimping, or other. The attachment mechanisms mayhave any suitable geometric configuration and may optionally includeapertures for receiving other components for coupling in vivo, such asan aperture for receiving a screw. Thus, for example, an attachmentmechanism may be provided configured for receiving an anchor forfixation to bone. Generally, any number of attachment mechanisms may beprovided at any suitable location on the covering.

The attachment mechanisms may be manufactured of the same material asthe portion of the covering to which it is coupled or may bemanufactured of a different material from the portion of the covering towhich it is coupled. The attachment mechanism may be resorbable ornonresorbable. The material of the attachment mechanism may be selectedto allow anchoring the covering to an adjacent covering having acomplementary attachment mechanism or to another structure. In variousembodiments, the attachment mechanism may comprise, allograft, syntheticmaterials, demineralized bone, nondemineralized bone, other material, orcombinations of these. The shape and size of the attachment mechanismmay be selected based on application.

In some embodiments, the covering may be tubular and have threaded endssuch that the ends may be threaded with a reciprocal thread of a furtherdevice or implant. For example, the covering may be used withinterference screws. In some embodiments, the covering may includeextensions or tabs that may be used for wrapping around or suturing tothe surgical site. Alternatively, the covering may be sutured directlyto the surgical site. The ends of the covering may be presealed or maybe sealed after introduction of contents. Sealing may be done by usingadhesives, heating, solvent treatment, suturing, knotting, or any othermeans.

Packing

The therapeutic agent may be packed in the covering at any suitabledensity. For some applications, the therapeutic agent may be looselypacked in the covering to enhance manipulability. In some embodiments,the material may be packed in the covering such that the coveringretains flexibility and may be folded over itself. In otherapplications, the therapeutic agent may be tightly packed in thecovering to provide a relatively stiff delivery system, and it may beweight bearing. In some embodiments, the covering may be configured tofacilitate placement of graft material in the covering as wasillustrated in FIGS. 1-3 described herein.

IV. Therapeutic agents for Delivery by Covering

A substance is provided inside the covering, before or during surgery(as described below), for delivery in vivo. Generally, the substance ormaterial may be homogenous or heterogeneous. The substance or materialmay be selected to exhibit certain gradients. For example, the substanceor material may be selected to exhibit a gradient to guide, lure, orattract cells along a pathway. Such gradient may comprise a cellgradient, a cell type gradient (for example transitioning from bonecells to cartilage cells or transitioning from bone cells to tendoncells), a gradient of conductivity, or a gradient of density/porosity.In some embodiments, the substance or material may comprise a sequenceof ingredients.

The covering may be used to deliver a substance comprising any suitablebiocompatible material. In specific embodiments, the covering may beused to deliver surface demineralized bone chips, optionally of apredetermined particle size, demineralized bone fibers, optionallypressed, and/or allograft. For embodiments wherein the substance isbiologic, the substance may be autogenic, allogenic, xenogenic, ortransgenic. Other suitable materials that may be positioned in thecovering include, for example, protein, nucleic acid, carbohydrate,lipids, collagen, allograft bone, autograft bone, cartilage stimulatingsubstances, allograft cartilage, TCP, hydroxyapatite, calcium sulfate,polymer, nanofibrous polymers, growth factors, carriers for growthfactors, growth factor extracts of tissues, demineralized bone matrix,dentine, bone marrow aspirate, bone marrow aspirate combined withvarious osteoinductive or osteoconductive carriers, concentrates oflipid derived or marrow derived adult stem cells, umbilical cord derivedstem cells, adult or embryonic stem cells combined with variousosteoinductive or osteoconductive carriers, transfected cell lines, boneforming cells derived from periosteum, combinations of bone stimulatingand cartilage stimulating materials, committed or partially committedcells from the osteogenic or chondrogenic lineage, or combinations ofany of the above. In some embodiments, the substance may be pressedbefore placement in the covering. A substance provided within thecovering may be homogenous, or generally a single substance, or may beheterogeneous, or a mixture of substances.

In some embodiments, the covering can comprise one or more compartmentshaving demineralized bone material therein. The demineralized bonematerial can be comprise demineralized bone, powder, chips, triangularprisms, spheres, cubes, cylinders, shards, fibers or other shapes havingirregular or random geometries. These can include, for example,“substantially demineralized,” “partially demineralized,” or “fullydemineralized” cortical and cancellous bone. These also include surfacedemineralization, where the surface of the bone construct issubstantially demineralized, partially demineralized, or fullydemineralized, yet the body of the bone construct is fully mineralized.In some embodiments, the covering may comprise some fully mineralizedbone material. The configuration of the bone material can be obtained bymilling, shaving, cutting or machining whole bone as described in forexample U.S. Pat. No. 5,899,939. The entire disclosure is hereinincorporated by reference into the present disclosure.

In some embodiments, the covering comprises elongated demineralized bonefibers having an average length to average thickness ratio or aspectratio of the fibers from about 50:1 to about 1000:1. In overallappearance the elongated demineralized bone fibers can be in the form ofthreads, narrow strips, or thin sheets. The elongated demineralized bonefibers can be substantially linear in appearance or they can be coiledto resemble springs. In some embodiments, the elongated demineralizedbone fibers are of irregular shapes including, for example, linear,serpentine or curved shapes. The elongated bone fibers can bedemineralized however some of the original mineral content may beretained when desirable for a particular embodiment.

In some embodiments, the covering comprises elongated demineralized bonefibers and chips. In some embodiments, the ratio of fibers to chips orpowders is from about 5, 10, 15, 20, 25, 30, 35, 40, or 45 fibers toabout 30, 35, 40, 45, 50, 55, 60, 65, or 70 chips.

In some embodiments, the biocompatible material comprises demineralizedbone matrix fibers and demineralized bone matrix chips in a 30:60 ratio.

In some embodiments, the demineralized bone material can be in thecovering and comprises from about 1 to about 70 micrometers particlesize range or from about 125 to about 250 micrometer particle sizerange.

In some embodiments, the covering may have a modulus of elasticity inthe range of about 1×10² to about 6×10⁵ dynes/cm², or 2×10⁴ to about5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm². After the cover isadministered to the target site, the covering may have a modulus ofelasticity in the range of about 1×−10² to about 6×10⁵ dynes/cm², or2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In some embodiments, the substance may be designed to expand in vivo.Such an embodiment may be used to fill a space and create contact withcongruent surfaces as it expands in vivo, for example for interbodyfusion. Thus, in some embodiments, the delivery system may be used inthe disc space, between implants, or inside a cage.

The covering retains the substance in place by pressure against thecovering. The covering thus may, in some embodiments, maintain particlesof substance in close proximity (for example, where the covering retainsa substance comprising bone particles). Generally, the ratio of coveringmaterial to substance for placement within the covering may be low. Forexample, in some embodiments, the ratio of covering material tosubstance, by weight, may be approximately 1:1,000, 1:100, 1:50, 1:25,1:1, or any suitable ratio that may be higher or lower than these.

In some embodiments the substance delivered by the covering may includeor comprise an additive such as an angiogenesis promoting material or abioactive agent. It will be appreciated that the amount of additive usedmay vary depending upon the type of additive, the specific activity ofthe particular additive preparation employed, and the intended use ofthe composition. The desired amount is readily determinable by oneskilled in the art. Angiogenesis may be an important contributing factorfor the replacement of new bone and cartilage tissues. In certainembodiments, angiogenesis is promoted so that blood vessels are formedat an implant site to allow efficient transport of oxygen and othernutrients and growth factors to the developing bone or cartilage tissue.Thus, angiogenesis promoting factors may be added to the substance toincrease angiogenesis. For example, class 3 semaphorins, for example,SEMA3, controls vascular morphogenesis by inhibiting integrin functionin the vascular system, and may be included in the recoveredhydroxyapatite.

In accordance with some embodiments, the substance may be supplemented,further treated, or chemically modified with one or more bioactiveagents (also referred to as therapeutic agents) or bioactive compounds(also referred to as therapeutic compounds). Bioactive agent orbioactive compound, as used herein, refers to a compound or entity thatalters, inhibits, activates, or otherwise affects biological or chemicalevents. For example, bioactive agents may include, but are not limitedto, osteogenic or chondrogenic proteins or peptides; demineralized bonepowder; collagen, insoluble collagen derivatives, etc., and solublesolids and/or liquids dissolved therein; anti-AIDS substances;anti-cancer substances; antimicrobials and/or antibiotics such aserythromycin, bacitracin, neomycin, penicillin, polymycin B,tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin,ampicillin, azactam, tobramycin, clindamycin and gentamycin, etc.;immunosuppressants; anti-viral substances such as substances effectiveagainst hepatitis; enzyme inhibitors; hormones; neurotoxins; opioids;hypnotics; anti-histamines; lubricants; tranquilizers; anti-convulsants;muscle relaxants and anti-Parkinson substances; anti-spasmodics andmuscle contractants including channel blockers; miotics andanti-cholinergics; anti-glaucoma compounds; anti-parasite and/oranti-protozoal compounds; modulators of cell-extracellular matrixinteractions including cell growth inhibitors and antiadhesionmolecules; vasodilating agents; inhibitors of DNA, RNA, or proteinsynthesis; anti-hypertensives; analgesics; anti-pyretics; steroidal andnon-steroidal anti-inflammatory agents; anti-angiogenic factors;angiogenic factors and polymeric carriers containing such factors;anti-secretory factors; anticoagulants and/or antithrombotic agents;local anesthetics; ophthalmics; prostaglandins; anti-depressants;anti-psychotic substances; anti-emetics; imaging agents;biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids;peptides; vitamins; inorganic elements; co-factors for proteinsynthesis; endocrine tissue or tissue fragments; synthesizers; enzymessuch as alkaline phosphatase, collagenase, peptidases, oxidases, etc.;polymer cell scaffolds with parenchymal cells; collagen lattices;antigenic agents; cytoskeletal agents; cartilage fragments; living cellssuch as chondrocytes, bone marrow cells, mesenchymal stem cells; naturalextracts; genetically engineered living cells or otherwise modifiedliving cells; expanded or cultured cells; DNA delivered by plasmid,viral vectors, or other means; tissue transplants; autogenous tissuessuch as blood, serum, soft tissue, bone marrow, etc.; bioadhesives; bonemorphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin(FN); endothelial cell growth factor (ECGF); vascular endothelial growthfactor (VEGF); cementum attachment extracts (CAE); ketanserin; humangrowth hormone (HGH); animal growth hormones; epidermal growth factor(EGF); interleukins, for example, interleukin-1 (IL-1), interleukin-2(IL-2); human alpha thrombin; transforming growth factor (TGF-beta);insulin-like growth factors (IGF-1, IGF-2); parathyroid hormone (PTH);platelet derived growth factors (PDGF); fibroblast growth factors (FGF,BFGF, etc.); periodontal ligament chemotactic factor (PDLGF); enamelmatrix proteins; growth and differentiation factors (GDF); hedgehogfamily of proteins; protein receptor molecules; small peptides derivedfrom growth factors above; bone promoters; cytokines; somatotropin; bonedigesters; antitumor agents; cellular attractants and attachment agents;immuno-suppressants; permeation enhancers, for example, fatty acidesters such as laureate, myristate and stearate monoesters ofpolyethylene glycol, enamine derivatives, alpha-keto aldehydes, etc.;and nucleic acids.

In certain embodiments, the bioactive agent may be a drug. In someembodiments, the bioactive agent may be a growth factor, cytokine,extracellular matrix molecule, or a fragment or derivative thereof, forexample, a protein or peptide sequence such as RGD.

In one embodiment of a covering comprising two compartments, a firstgrowth factor may be provided for delivery by the first compartment anda second growth factor may be provided for delivery by the secondcompartment. The first and second growth factors may be provided withother substances. The first and second growth factors may be selected(and placed in respective compartment for positioning in vivo) based ondesired characteristics of the growth factor. For example, an angiogenicgrowth factor may be provided in the first compartment and anosteoinductive growth factor may be provided in the second compartment.

Similarly, the substance delivered by the first compartment and thesubstance delivered by the second compartment may be selected based ondesired characteristics of the compartment according to its placement invivo. Thus, for example, one compartment may have a substance that issubstantially osteoclast stimulating while another compartment may havea substance that is substantially osteoblast stimulating.

In one embodiment, demineralized bone fibers may be provided in thefirst compartment and surface demineralized bone chips may be providedin the second compartment. In this embodiment, the demineralized bonefibers may generally provide osteoinductive characteristics and thesurface demineralized chips may generally provide osteoinductive and/orosteoconductive characteristics. In use, the covering may be laid flaton the transverse process and positioned such that the firstcompartment, holding the demineralized bone fibers, is nearest thevertebral body and the second compartment, holding the surfacedemineralized bone chips, is farther from the vertebral body, or thecompartments may be positioned in any other desired configuration. Inanother embodiment, a covering may comprise first and secondcompartments wherein autograft may be placed in one of the compartmentsprior to placement of the covering in vivo, described more fully below.In other embodiments, three or more compartments may be used, asappropriate for the materials being delivered and the application of thecompartmented implant. More than one substance may be provided in acompartment. For example, surface demineralized bone chips anddemineralized bone fibers may be mixed and provided within a singlecompartment. Such mixture of substances within a single compartment maybe a substantially uniform mix or may be a plurality of substancesplaced in the compartment separately such that they are substantiallyunmixed. When multiple compartments are used, each compartment maycontain one or more substances. Exemplary substances that may beprovided in one or more compartments of the delivery system includecells from the osteogenic precursors, growth factors, angiogenic factorsand other active proteins including bone morphogenic proteins, andcellular scaffolding materials of natural or synthetic origin,antibiotics, and other substances described below.

In some embodiments, other medical devices may be provided within thecovering. For example, one or more electrical stimulator electrodes maybe provided within the covering.

Sterilization

The medical device and/or covering may be sterilizable. In variousembodiments, one or more components of the medical device and/orcovering are sterilized by radiation in a terminal sterilization step inthe final packaging. Terminal sterilization of a product providesgreater assurance of sterility than from processes such as an asepticprocess, which require individual product components to be sterilizedseparately and the final package assembled in a sterile environment.

In various embodiments, gamma radiation is used in the terminalsterilization step, which involves utilizing ionizing energy from gammarays that penetrates deeply in the device and/or covering. Gamma raysare highly effective in killing microorganisms, they leave no residuesnor have sufficient energy to impart radioactivity to the device. Gammarays can be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device and/or covering. E-beamradiation comprises a form of ionizing energy, which is generallycharacterized by low penetration and high-dose rates. E-beam irradiationis similar to gamma processing in that it alters various chemical andmolecular bonds on contact, including the reproductive cells ofmicroorganisms. Beams produced for e-beam sterilization areconcentrated, highly-charged streams of electrons generated by theacceleration and conversion of electricity. E-beam sterilization may beused, for example, when the medical device and/or covering is includedin a gel.

Other methods may also be used to sterilize the device and/or coveringand/or one or more components of the device and/or covering, including,but not limited to, gas sterilization, such as, for example, withethylene oxide or steam sterilization.

Methods of Use

The covering delivers the substance or substances in vivo. Such deliverymay be active, passive, by diffusion, or other. Active delivery mayinclude the degradation or decomposition of the covering with theinteraction of body fluids, extracellular matrix molecules, enzymes orcells. It may also include the cleavage of physical and/or chemicalinteractions of substance from covering with the presence of bodyfluids, extracellular matrix molecules, enzymes or cells. Further, itmay comprise formation change of substances (growth factors, proteins,polypeptides) by body fluids, extracellular matrix molecules, enzymes orcells.

The covering is loaded with the substance for placement in vivo. Thecovering may be pre-loaded, thus loaded at manufacture, or may be loadedin the operating room or at the surgical site. Preloading may be donewith any of the substances previously discussed including, for example,DBM, synthetic calcium phosphates, synthetic calcium sulfates, enhancedDBM, collagen, carrier for stem cells, and expanded cells (stem cells ortransgenic cells). Any other suitable method may be used for loading asubstance in the covering in the operating room or at the surgical site.For example, the substance may be spooned into the covering, thesubstance may be placed in the covering using forceps, the substance maybe loaded into the covering using a syringe (with or without a needle),or the substance may be inserted into the covering in any other suitablemanner. Specific embodiments for loading at the surgical site includefor vertebroplasty or for interbody space filler.

In various embodiments, loading in the operating room or at the surgicalsite can be done with any of these materials and further with autograftand/or bone marrow aspirate by adding the desired material through thefilling means or funnel 400 by gravity using a spoon and/or a plunger topush the material through. For example, the surgeon can grasp thecovering or bag 102 depicted in FIG. 1 and proceed to load compartment108 with autograft via funnel 400 through opening 120 of covering 102.Thereafter, once compartment 108 is full, funnel 400 is removed anddrawstrings 116 and 118 can also be removed by pulling them off from thedevice. Once drawstrings 116 and 118 are removed, bag flap 122 is sealedclosed and DBM and autograft particles can be thoroughly mixed incovering or bag 102 thereby optimizing the biological environment forinducing new bone growth at the selected surgical site.

For placement, the substance or substances may be provided in thecovering and the covering placed in vivo. In one embodiment, thecovering is placed in vivo by placing the covering in a catheter ortubular inserter and delivering the covering with the catheter ortubular inserter. The covering, with a substance provided therein, maybe steerable such that it can be used with flexible introducerinstruments for, for example, minimally invasive spinal procedures. Forexample, the osteoimplant may be introduced down a tubular retractor orscope, during XLIF, TLIF, or other procedures. In other embodiments, thecovering (with or without substance loaded) may be placed in a cage, forexample for interbody fusion.

In continuous tube embodiments, the surgeon may divide the tube into thedesired number of compartments, using a crimper, heat tool or other.Alternatively, in an embodiment wherein the tube is perforated into aplurality of compartments, the surgeon may select the number ofcompartments desired and cut along the applicable perforation. In someembodiments, some of the compartments may be prefilled with a substancefor delivery and other compartments may be empty for filling by thesurgeon. For example, ever other compartment between perforations may bepreloaded or filled. The osteoimplant thus may be customized by fillingthe empty compartments with a desired substance.

Attachment mechanisms provided on the covering may be used to couple thecovering to a site in vivo.

The covering may be used in any suitable application. In someembodiments, the covering may be used in healing vertebral compressionfractures, interbody fusion, minimally invasive procedures,posterolateral fusion, correction of adult or pediatric scoliosis,treating long bone defects, osteochondral defects, ridge augmentation(dental/craniomaxillofacial, e.g. edentulous patients), beneath traumaplates, tibial plateau defects, filling bone cysts, wound healing,around trauma, contouring (cosmetic/plastic/reconstructive surgery), andothers. The delivery system may be used in a minimally invasiveprocedure via placement through a small incision, via delivery through atube, or other. The size and shape may be designed with restrictions ondelivery conditions. In some embodiments, pieces of the covering can beseparated by pulling or tearing force applied along separation assistsif present in a multi compartment configuration and the pieces of thecovering can be used to surround the bone defect. For examples, 3 piecesof the torn covering can be placed around the bone defect to triangulatebone growth by the influx of cells, in, at or near the bone defect.

In some embodiments, the covering is flexible enough so that thecovering can be folded upon itself before it is implanted at, near or inthe bone defect.

An exemplary application for using a delivery system as disclosed isfusion of the spine. In clinical use, the covering and deliveredsubstance may be used to bridge the gap between the transverse processesof adjacent or sequential vertebral bodies. The delivery system may beused to bridge two or more spinal motion segments. The coveringsurrounds the substance to be implanted, and contains the substance toprovide a focus for healing activity in the body.

In other applications, the delivery system may be applied to transverseprocesses or spinous processes of vertebrae.

Generally, the delivery system may be applied to a pre-existing defect,to a created channel, or to a modified defect. Thus, for example, achannel may be formed in a bone, or a pre-existing defect may be cut toform a channel, for receipt of the delivery system. The covering may beconfigured to match the channel or defect. In some embodiments, theconfiguration of the covering may be chosen to match the channel. Inother embodiments, the channel may be created, or the defect expanded oraltered, to reflect a configuration of the covering. The covering may beplaced in the defect or channel and, optionally, coupled usingattachment mechanisms.

At the time just prior to when the delivery system is to be placed in adefect site, optional materials, for example, autograft bone marrowaspirate, autograft bone, preparations of selected autograft cells,autograft cells containing genes encoding bone promoting action, can becombined with the covering and/or with a substance provided within thecovering prior to or during the surgical procedure. The osteoimplant canbe implanted at the bone repair site, if desired, using any suitableaffixation means, for example, sutures, staples, bioadhesives, screws,pins, rivets, other fasteners and the like or it may be retained inplace by the closing of the soft tissues around it.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. A delivery system comprising a covering having atleast two compartments, a first compartment containing a firsttherapeutic agent and a second compartment configured to receive asecond therapeutic agent, wherein the covering retains the firsttherapeutic agent for mixing with the second therapeutic agent prior todelivery at a surgical site.
 2. A delivery system according to claim 1,wherein the covering comprises a porous mesh and the second compartmentis unfilled.
 3. A delivery system according to claim 1, wherein thefirst compartment and the second compartment are separated by at leastone removable separation member.
 4. A delivery system according to claim3, wherein the at least one removable separation member comprises apullstring or drawstring.
 5. A delivery system according to claim 1,wherein the second compartment defines an opening further comprising apre-attached sealing member.
 6. A delivery system according to claim 1,wherein the sealing member comprises a flap, sutures, pressing fittingor interference fitting, heat seals or combinations thereof.
 7. Adelivery system according to claim 1, further comprising an attachablefilling member configured to fit onto the second compartment.
 8. Adelivery system according to claim 7, wherein the delivery systemfurther comprises an attachment element cooperatively attached to thefilling member or the second compartment for maintaining the secondcompartment open for filling with the second therapeutic agent.
 9. Adelivery system according to claim 8, wherein the attachment elementcomprises a spring loaded clip, a friction fitting or an interferencefitting.
 10. A delivery system according to claim 1, wherein the firsttherapeutic agent comprises demineralized bone matrix and the secondtherapeutic agent comprises protein, carbohydrate, lipid, collagen,allograft bone, autograft bone, tricalcium phosphate, hydroxyapatite, agrowth and differentiation factor, a carrier for a growth factor, agrowth factor extract of tissue, bone marrow aspirate, concentrates oflipid derived or marrow derived adult stem cells, umbilical cord derivedstem cells, committed or partially committed cells from osteogenic orchondrogenic lineage, an antimicrobial, an antibiotic, a statin, orcombinations thereof.
 11. A delivery system comprising a coveringconfigured for implantation into a bone defect site, the covering havingat least two compartments, a first compartment containing a firsttherapeutic agent and a second unfilled compartment configured toreceive a second therapeutic agent, wherein the covering retains thefirst therapeutic agent for mixing with the second therapeutic agentprior to delivery at a surgical site, the at least two compartmentsbeing separated by at least one removable separation member, the secondcompartment defining an opening further comprising a pre-attachedsealing member.
 12. A delivery system according to claim 11, wherein theremovable separation member comprises a pull string and the pre-attachedsealing member comprises a flap.
 13. A delivery system according toclaim 11, further comprising an attachable filling member configured tofit onto the second unfilled compartment and an attachment elementcooperatively attached to the filling member or the second unfilledcompartment for maintaining the second unfilled compartment open forfilling with the second therapeutic agent, wherein the attachmentelement comprises a spring loaded clip, a friction fit or aninterference fit.
 14. A delivery system according to claim 10, whereinthe covering comprises a porous mesh.
 15. A method of treating a bonedefect in a patient in need of such treatment, the method comprisingimplanting into the bone defect a delivery system according to claim 3.16. A method of treating a bone defect according to claim 15, furthercomprising mixing of the first and second therapeutic agents by removingthe removable separation member.
 17. A method of treating a bone defectaccording to claim 15, further comprising shrinking the delivery systemby removing the removable separation member.
 18. A method of treating abone defect according to claim 13, further comprising attaching afilling member to the second compartment.
 19. A method for treating abone defect according to claim 15, further comprising filling the secondcompartment with a second therapeutic agent.
 20. A method for treating abone defect according to claim 15, wherein the first therapeutic agentcomprises demineralized bone matrix and the second therapeutic agentcomprises protein, carbohydrate, lipid, collagen, allograft bone,autograft bone, tricalcium phosphate, hydroxyapatite, a growth anddifferentiation factor, a carrier for a growth factor, a growth factorextract of tissue, bone marrow aspirate, concentrates of lipid derivedor marrow derived adult stem cells, umbilical cord derived stem cells,committed or partially committed cells from osteogenic or chondrogeniclineage, an antimicrobial, an antibiotic, a statin, or combinationsthereof.